Open Access is an initiative that aims to make scientific research freely available to all. To date our community has made over 100 million downloads. It’s based on principles of collaboration, unobstructed discovery, and, most importantly, scientific progression. As PhD students, we found it difficult to access the research we needed, so we decided to create a new Open Access publisher that levels the playing field for scientists across the world. How? By making research easy to access, and puts the academic needs of the researchers before the business interests of publishers.

We are a community of more than 103,000 authors and editors from 3,291 institutions spanning 160 countries, including Nobel Prize winners and some of the world’s most-cited researchers. Publishing on IntechOpen allows authors to earn citations and find new collaborators, meaning more people see your work not only from your own field of study, but from other related fields too.

Abstract

The chemical structure of quinazolinones includes benzene ring fused with 2-pyrimidinone (1), 4-pyrimidinone (2) or 2,4-pyrimidinedione (3) ring, and are named as quinazolin-2(1H)-one, quinazolin-4(3H)-one or quinazolin-2,4(1H, 3H)-one, respectively. The chemical structure of quinazolinones constitutes a crucial scaffold of natural and synthetic compounds with various therapeutic and biological activities. Quinazolinones are first synthesized by Stefan Niementowski (1866–1925) and named after Niementowski quinazolinone synthesis. Quinazolinones have strongly attracted the interest of medicinal chemist as they constitute a large class of compounds that exhibited broad spectrum of biological activities including antimicrobial, antimalarial, anticonvulsant, anticancer, antileishmanial, anti-inflammatory, etc. This chapter provides a brief overview on the recent advances on chemical and pharmacological aspects of quinazolinone derivatives published in the last decade.

From the Edited Volume

1. Introduction

Heterocyclic compounds are organic cyclic compounds having at least one atom other than carbon in their ring structures. Quinazolinones are formed by fusion of benzene ring with 2-pyrimidinone (1), 4-pyrimidinone (2) or 2,4-pyrimidinedione (3) ring, and are named as quinazolin-2(1H)-one, quinazolin-4(3H)-one or quinazolin-2,4(1H, 3H)-one, respectively ( Figure 1 ).

2. Synthetic methods of quinazolinones

The number of synthetic methods of quinazolinone cores has intensely increased from year to year. These advancements in methods of synthesis lead to the access to new and effective quinazolinone compounds with augmented structural diversity starting from affordable and easily accessible substrates. In this chapter, we depict different methods of synthesis of quinazolinone derivatives from cheap and readily available starting precursors.

2.1 Synthesis of quinazolinone compounds from 2-aminobenzoic acid

Quinazolin-4(3H)-one (4) was synthesized by the reaction of formamide with 2-aminobenzoic acid at 125–130°C and cyclization of 2-aminobenzoic acid takes place as described in Figure 2 [23]. Synthetic works started from esterification of 2-aminobenzoic acid and subsequently followed by reaction with isocyanates afforded 1,3-disubstituted quinazol-2,4(1H, 3H)-diones (5) [24] ( Figure 2 ). 2-mercapto-3-substituted quinazolin-4(3H)-one derivatives (6) ( Figure 2 ) have been synthesized through the interaction between 2-aminobenzoic acid and corresponding isothiocyanate reagent.

Figure 2.

Synthesis of quinazolin-4(3H) one from 2-aminobenzoic acid.

In 1960, Ried et al. reported [25, 26, 27] the reaction of imidates and 2-aminobenzoic acid in methanol at 80°C to afford the desired quinazolinones (7) in good yields ( Figure 2 ).

A recently reported route, to the synthesis of 2-substituted quinazolin-4(3H)-ones (7) under microwave conditions was reported by Rad-Moghadam and Mohseni [28]. This approach involves the condensation of 2-aminobenzoic acid, orthoesters and ammonium acetate which afford the 2-substituted-4(3H)-quinazolinone (7) Figure 2 .

A solvent-free approach was reported by Li et al. [29] for the synthesis of 2,3-disubstituted-4(3H)-quinazolinones (8). The approach involves the interaction between 2-aminobenzoic acid, acyl chlorides and aromatic/aliphatic amines in the presence of SO3H-functionalized Brønsted acid ionic liquids as a catalyst under microwave irradiation ( Figure 2 ). Langer and Döring [30] reported the reaction of 2-aminobenzoic acids with oxalic acid bis(imidoyl) chlorides to prepare quinazolinones (9) Figure 2 .

2.2 Synthesis of quinazolinone compounds from 2-aminobenzamide

In 1962, Bake and Almaula [31] have reported the synthesis of 2-carboethoxy-quinazoline-4(3H)-one 10 through the reaction of anthranilamide and diethyl oxalate ( Figure 3 ). Shaterian and Rigi [32] reported a starch sulfate-catalyzed method for synthesis of 2-substituted-1,2,3,4-tetrahydro-4-quinazolinones 11 ( Figure 3 ). Zhang and co-workers [33] reported a MnO2-catalyzed method for the synthesis of 2-substituted quinazolinones 12. Anthranilamides undergo a-MnO2-catalyzed oxidative cyclization with alcohols using TBHP as an oxidant ( Figure 3 ). Compound 12 could be obtained through the condensation of anthranilamide with an aldehyde in refluxing ethanol in the presence of CuCl2 [34]. Schiff base intermediate was first obtained and, in turn, is transformed into the 2-substituted quinazolinones 12 ( Figure 3 ).

Figure 3.

Synthesis of quinazolin-4(3H) one from 2-aminobenzamide.

In 1887, when Körner reported that the acylation of anthranilamide results in diamide intermediate which upon treatment with sodium carbonate or sodium hydroxide yielded 2-phenylquinazolin-4(3H)-one 12( Figure 3 ) [35].

Quinazolin-4(3H) one compound 12 have been developed by Yang et al. via selective cleavage of the triple bond of ketoalkynes. A reasonable mechanism was suggested for this reaction ( Figure 3 ). Michael addition of the amino group of the anthranilamide to the triple bond of the ketoalkyne generated the enaminone intermediate which upon acid catalyzed intramolecular cyclization with subsequent C-C bond cleavage afforded final product 12.

Wang and Ganesan [45] reported the synthesis of luotonin A, 23 through the reaction of anthranilic acid with 1H-pyrrolo[2,3-b]quinolin-2(3H)-one ( Figure 6 ).

3. Biological applications of quinazolinones

Natural quinazolinones that widely used in traditional folk medicines are isolated from the plants and microorganisms while the major quinazolinone derivatives are accessed through synthetic process by some chemical reactions. Quinazolinone compounds constitute most privileged class of biologically active heterocyclic compounds. Because of their wide spectrum of biological activities, quinazolinones either from natural source or from synthetic origin, have prompted the medicinal chemist for structural design of these active compounds to develop high selective and potent pharmacological activities.

3.1 Anticancer activity

The natural cytotoxic quinazolinones are depicted in Figure 7 . The Chinese herbal medicinal plant, Luotonin A 23, Figure 7 is a cytotoxic natural alkaloid possessing pentacyclic fused-quinazolinone moiety. It was first isolated from Peganum migellastrum in 1997 and it is in clinical use as anticancer agent and showed low human human topoisomerase-I inhibitor activity [46].

Figure 7.

Chemical structure of anticancer compounds.

Topoisomerases being major targets for anticancer drug design, the luotonin A was used as a lead compound for development of analogs with increased potency [47]. In comparison with the luotonin A, the majority derivatized analogs explored higher activity for topoisomerase I inhibition and better in vitro cytotoxicity than lutonin A [47]. In view of these results, luotonin A is considered as a pharmacophoric core for the design of new topoisomerase I inhibitors [48].

3.2 Anti-inflammatory activity

The inflammation is a biochemical reactions response that protects the body from infection and injury. It reflects the response of the organism to various stimuli and is related to many disorders such as arthritis, asthma and psoriasis which require prolonged or repeated treatment. The major cause of inflammation the release of chemicals from tissues such as the prostaglandins, histamine, leukotrienes, bradykinin, platelet-activating factor and interleukin-1. Corticosteroids inhibit the synthesis of both PGs and LTs through the release of lipocortin, which inhibits phospholipase A2 and subsequently reduces arachidonic acid release alleviating the inflammation of either rheumatoid arthritis or asthma. While nonsteroidal anti-inflammatory drugs NIASID relieve the inflammation through the inhibition of the cyclooxygenase enzyme and reducing the synthesis of prostanoids [62]. Figure 8 shows the chemical structure of the anti-inflammatory quinazolinone compounds. Spiro [(2H,3H) quinazoline-2,10-cyclohexan]-4(1H)-one compounds 40 and 41 were reported as potent anti-inflammatory and analgesic activity of superior GIT safety margin in rats model compared with indomethacin (10 mg/kg) and tramadol (20 mg/kg) as reference standards [63].

3.3 Anticonvulsant activity

Epilepsy is defined a chronic neurological syndromes and marked by neuronal firing and neuronal hyperexcitability. Although, the available antiepileptic therapeutics explore satisfactory seizure control in about 70% of epileptic patients, it has become very urgent to search for new antiepileptic compounds with fewer side-effects and less toxicity.

A series of novel 3-[5-substituted phenyl-1,3,4-thiadiazole-2-yl]-2-styryl quinazoline-4(3H)-one derivatives has been synthesized by Jatav et al. [73]. Of this series, compounds 55 and 56 revealed anticonvulsant activity results at 0.5 and 4 h in both MES and scPTZ test models, whereas compound 57 explored anticonvulsant activity results at 4 h in MES model and at 0.5 and 4 h in scPTZ model.

3.4 Antimicrobial activity of quniazolinones

2-oxo-azetidinyl-quinazolin-4(3H)-ones (58) possess antimicrobial activity against S. aureus, B. subtilis, E. coli and C. albicans [74]. 2-Mercapto-3-(4-chlorophenyl)-6-iodo-3H-quinazolin-4-one derivatives (59–62) were reported to show a significant antimicrobial activity and could be useful as lead compounds for further design and discovery of more potent antimicrobials [75].

Figure 10.

Chemical structure of antimicrobial compounds.

3.5 Antimalarial activity

Malaria is a parasitic disease caused by Plasmodium species parasite. It is widespread in several regions in Africa, Asia and South America. These parasites have developed a drug resistance to almost all the commercially available antimalarial drugs. The good antimalarial potency and the less side effects of quinazolinone compounds promote the researchers for the development of new antimalarial compounds [80].

In 1948, Febrifugine (74), a Chinese traditional herb, has been extracted from leaves of Dichroa febrifuga that was found in the garden plant Hydrangea. It has 50–100 times as antimalarial as quinine in in vivo model. Febrifugine analogues WR140085 (75), WR090212 (76), WR146115 (77) were reported as potent antimalarial agents. The gastrointestinal side effects of (74) and the macrophage cells mediated clearance of (75–77) requested further therapeutic development and discovery of new antimalarial drugs [2]. Birhan et al. [81] have synthesized 3-aryl-2-(substituted styryl)-4(3H)-quinazolinone derivatives (78, 79) as potent antimalarial agents ( Figure 11 ).

Figure 11.

Antimalarial compounds.

3.6 Antiviral activity

Wang et al. [82] reported quinazolinone derivatives (80, 81) with potent antiviral activity against HIV and TMV. Gao et al. [83] have synthesized a series of 2-aryl- or 2-methyl-3-(substituted benzalamino)-4(3H)-quinazolinone derivatives and found that the compounds (82) and (83) exhibit good antiviral activity against TMV ( Figure 12 ).

Figure 12.

Antiviral compounds.

Liu et al. [84] reported a series of 2-pyridinyl-3-substituted-4(3H)-quinazolinones as anti-influenza A virus agents. Of these derivatives, compounds (84–87) revealed potent activity (IC50 = 51.6–93.0 μM) better than that of the clinically used drug, ribavirin. Also, it was reported that compound (87) could inhibit influenza A virus propagation through inhibition of cellular NF-kB pathway, although it was not as effective as ribvarin ( Figure 12 ).

3.7 Cathepsin inhibitor activity

Cathepsins B and H are cysteine proteases that plays a major role in cancer progression as they degrade extracellular matrices facilitating invasion, angiogenesis and metastasis. Therefore the research community has been prompted to the discovery of potent cathepsins inhibitor hemotherapeutics [85].

Singh and Raghav [86] reported the synthesis of a series of 2,3-dihydroquinazolin-4(1H)-ones and evaluated it as cathepsins inhibitors, Figure 13 . Of these compounds, 2-(4-fluorophenyl)-2,3-dihydroquinazolin-4(1H)-one (88; R = F) and 2-(4-chlorophenyl)-2,3-dihydro quinazolin-4(1H)-one (88; R = Cl) substituted compounds showed maximum inhibition on cathepsin B. Whereas for cathepsin H, 2,3-dihydro-2-(4-methylphenyl)quinazolin-4(1H)-one (88; R = Me) and 2-(4-fluorophenyl)-2,3-dihydroquinazolin-4(1H)-one (88; R = F) have been found to be the most potent inhibitors.

3.8 Topoisomerase inhibitor activity

The DNA replication process is controlled essentially by DNA topoisomerase I (Top1) through the relaxation of the nucleic acid’s supercoiled structure. Basically, DNA Top1 attracts the interests of research community as a cancer chemotherapy target [88]. Efforts to overcome side effects of these clinically used anticancer Top1 inhibitors, particularly bladder toxicity, had led to the development of luotonin A alkaloid and discovery of its Top1 inhibitory activity [89].

Ibric et al. reported the development of novel luotonin A isomeric congeners bearing an amino at positions 1, 2, 3, and 4, (93–97) Figure 14 [90]. These compounds revealed significant profile of cytotoxic activity and G2/M cell cycle arrest, proposing either Top1 is not the only target, or some atypical mechanism is accountable for inhibition of Top1 enzyme.

Kamata et al. have prepared series of pyrimidoacridones (101), Pyrimidocarbazoles (102) and pyrimidophenoxadines (103) ( Figure 14 ), and as topoisomerase II inhibitors [92]. Against P388 and KB cell lines, pyrimidocarbazoles and pyrimidophenoxadines were more potent than pyrimidoacridines. Pyrimidocarbazoles inhibited the in vivo tumor growth of mouse sarcoma M5076 with T/C values of 42% at 3.13 mg/kg/d, and increased the level of DNA-topo II cross-linking in P388 cells.

3.9 α-Glucosidase inhibitor activity

Diabetes is a reduced ability to convert glucose into energy inside the body. The role of insulin is the glucose transfer from blood into cells. A large number of antidiabetic agents with different mechanism of action are available in the market.

3.10 Thymidine synthase inhibitor activity

Thymidylate synthase enzyme (TS) plays a crucial role in the DNA biosynthesis that it catalyzes the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP), one of the nucleotides that constitute the DNA. Inhibition of TS results in imbalance of deoxynucleotides that increase the level of dUMP and finally leads to DNA damage [97]. TS is considered as interesting chemotherapeutic target for treatment of pancreatic, colorectal, ovarian, breast and gastric cancers [98].

In 1998, raltitrexed (117) a quinazolin-4-(1H)-one compound that has been clinically approved by EMA for treatment of colorectal cancer. Also, pemetrexed (118) is a quinazolin-4(1H)-one compound that is clinically approved by EMA and FDA in 2001. Both raltitrexed and pemetrexed are considered as classical antifolates as they are folate analogs containing a pterin ring and a charged glutamate tail, therefore they need active internalization into the cells through folate carrier system [99].

Figure 16.

Thymidine synthase and phosphorylase inhibitors.

3.11 Monoamine oxidase inhibitor activity (MAO)

In human, monoamine oxidases (MAOs) are mitochondrial bound enzymes that are responsible for oxidative deamination metabolism of neurotransmitters such as dopamine, serotonin, norepinephrine and epinephrine. In the brain, MAO-A enzyme isoform metabolizes serotonin, therefore specific MAO-A inhibitors are used the treatment of anxiety and depression disorder [103]. On the other hand, MAO-B enzyme metabolizes dopamine in the brain thus MAO-B specific inhibitors are prescribed for the treatment of Parkinson’s disease [104].

Quinazolinone moiety, one of numerous MAO inhibitor scaffolds, it has been explored as lead for the further development of potent MAO inhibitors. Compounds (123–127; Figure 17 ) are representative MAO-inhibitor examples of 4(3H)-quinazolinones [105].

Figure 17.

Chemical structure of monoamine oxidase (MAO) inhibitors.

Qhobosheane et al. reported seven quinazolinone compounds (IC50 < 1 μM) ascertained as potent and specific MAO-B inhibitors, among them the most potent inhibitor, 2-[(3-iodobenzyl)thio]quinazolin-4(3H)-one (128; Figure 17 ), with IC50 value of 0.142 μM. Although these derivatives have been proved as reversible and competitive MAO-B inhibitor (Ki = 0.068 μM), none of the them were MAO-A inhibitors [106].

4. Marketed quinazolinone drugs

Proquazone is non-steroidal anti-inflammatory drug (Biarison®) (132; Figure 18 ) manufactured by Novartis pharmaceutical company. Also, it is used in the treatment of degenerative joint disease.

Figure 18.

Chemical structure of marketed quinazolinone drugs.

Nolatrexed [108] compound (133; Figure 18 ) is a thymidylate synthase inhibitor drug manufactured by Agouron pharmaceutical company under trade name Thymitaq®. In 1998, Zarix licensed Thymitaq® from Agouron. It is used in treatment of liver cancer.

Quinethazone or Hyromox® [109] (134; Figure 18 ) has been marketed as antihypertensive drug by Lederle pharmaceutical company and was recently withdrawn from the market.

Fenquizone’s brand name is Idrolone® (135; Figure 18 ) [110], it is marketed by Maggioni pharmaceutical company. It is a low-ceiling diuretics used in the treatment of oedema and hypertension.

The brand name of albaconazole [111] is Albaconazole® (136; Figure 18 ). It was marketed by GlaxoSmithKlyne pharmaceutical company as an oral and topical antifungal agent.

The brand name of afloqualone is Arofuto® (138; Figure 18 ) [113]. It is marketed by Mitsubishi Tanabe Pharma pharmaceutical company as sedative and muscle relaxant drug.

Evodiamine (139; Figure 18 ) [114] has been isolated from the Evodia plants and was found to reduce fat uptake in animal model. It is used for bodybuilding as over the counter supplements.

5. Conclusions

This chapter depicts different methods of synthesis of quinazolinone derivatives starting from affordable and easily accessible substrates including 2-aminobenzoic acid, 2-aminobenzamide, o-substituted aniline in addition to the synthetic methods of spiroquinazolinones and heterocycle-fused quinazolinones. Also, the chapter discusses different biological applications of both natural and synthetic quinazolinones. The last section in this chapter lists common quinazolinone drugs that have been approved in the market.

Acknowledgments

This book chapter was supported by King Saud University, Vice Deanship of Research Chairs, Kayyali Chair for Pharmaceutical Industry, through grant number AW-2019.

Synthesis of Quinazoline and Quinazolinone Derivatives

Related Book

Nonsteroidal Anti-Inflammatory Drugs

Introductory Chapter - The Newest Research in Nonsteroidal Anti-inflammatory Drugs

By Ali Gamal Al‐kaf

We are IntechOpen, the world's leading publisher of Open Access books. Built by scientists, for scientists. Our readership spans scientists, professors, researchers, librarians, and students, as well as business professionals. We share our knowledge and peer-reveiwed research papers with libraries, scientific and engineering societies, and also work with corporate R&D departments and government entities.